1. Field of the Invention
The present invention relates generally to the fields of biochemical endocrinology and regulation of bone formation and degradation. More specifically, the present invention relates to regulation of osteoclast formation by inhibition of osteoblastic stem cell factor.
2. Description of the Related Art
The human skeleton is continuously remodeled, normally turning over in .about.2 years and allows use of skeletal mineral in calcium homeostasis. The strength and shape of the skeleton is preserved by segmental replacement: a bone section is degraded by osteoclasts, formed from monocyte-macrophage precursors,.sup.1-2 while osteoblasts, derived from stromal cells,.sup.3 synthesize new bone. These unrelated cells differentiate in a coupled manner, producing a new bone section in a few weeks.
Overall bone turnover responds to parathyroid hormone, but how differentiation of osteoblasts and osteoclasts is coordinated locally to maintain bone integrity is poorly understood. Osteoclast differentiation requires that precursors contact osteoblast-like cells,.sup.4 suggesting specialized recognition molecules. In situ unlabeled antibody and Western blot analysis revealed that osteoblasts express a surface-bound form of stem cell factor (SCF; c-kit ligand) during bone synthesis only. Stem cell factor production in isolated osteoblasts responds to parathyroid hormone. Differentiation of osteoclasts from monocytes is supported by osteoblast-derived stem cell factor-producing cells in vitro, a process interrupted by antibody or antisense oligonucleotide targeting stem cell factor, indicating that it is a key element controlling this process.
The SCF/kit signaling pathway is very complex. Briefly summarized, stem cell factor binding induces receptor dimerization, which is associated with phosphorylation. Activity is transduced through intracellular kinases of the src family, the oncogene c-Cbl and pI-3 kinase. Src and Cbl are required for osteoclast differentiation; src, Cbl and PI-3-kinase interact with other osteoclast signaling molecules.
When ionized calcium is suppressed, such as with retention of phosphate in kidney failure, parathyroid hormone is secreted in large quantities and bone turnover increases as much as ten-fold, coupling of bone formation and degradation is maintained. Occurrence of stem cell factor in bone of hyperparathyroid subjects was examined because abnormal mast cell differentiation occurs around bone trabeculae of these patients,.sup.5 and this protein causes mast cell differentiation in vitro..sup.6 Stem cell factor is expressed in a variety of forms in several tissues,.sup.7 with a soluble form produced by a six-exon transcript and a longer membrane-associated form produced by an eight-exon transcript..sup.8 Additional variation occurs with proteolytic cleavage and glycosylation.
The prior art is deficient in the lack of effective means of inhibiting osteoclast formation and activity and thereby regulating bone formation and/or degradation. The present invention fulfills this longstanding need and desire in the art.